Insulin’s old flame

Both the immune system and metabolism are known to be dysregulated in aging; however, any link between the two is not well understood. Here, Bodogai et al. showed in aged mice and nonhuman primates that aging-associated insulin resistance may be mediated by changes in the gut microbiome. Age-induced gut permeability, which the authors tied to a reduction in intestinal butyrate and subsequent loss of Akkermansia muciniphila, led to increased leakage of proinflammatory factors. These factors activated monocytes, which, in turn, caused B1a cells to express 4-1BBL, resulting in impaired insulin signaling. Future studies will determine whether a microbiome-inflammatory-metabolic axis is targetable in aging or disease.

Abstract

Aging in humans is associated with increased hyperglycemia and insulin resistance (collectively termed IR) and dysregulation of the immune system. However, the causative factors underlying their association remain unknown. Here, using “healthy” aged mice and macaques, we found that IR was induced by activated innate 4-1BBL+ B1a cells. These cells (also known as 4BL cells) accumulated in aging in response to changes in gut commensals and a decrease in beneficial metabolites such as butyrate. We found evidence suggesting that loss of the commensal bacterium Akkermansia muciniphila impaired intestinal integrity, causing leakage of bacterial products such as endotoxin, which activated CCR2+ monocytes when butyrate was decreased. Upon infiltration into the omentum, CCR2+ monocytes converted B1a cells into 4BL cells, which, in turn, induced IR by expressing 4-1BBL, presumably to trigger 4-1BB receptor signaling as in obesity-induced metabolic disorders. This pathway and IR were reversible, as supplementation with either A. muciniphila or the antibiotic enrofloxacin, which increased the abundance of A. muciniphila, restored normal insulin response in aged mice and macaques. In addition, treatment with butyrate or antibodies that depleted CCR2+ monocytes or 4BL cells had the same effect on IR. These results underscore the pathological function of B1a cells and suggest that the microbiome–monocyte–B cell axis could potentially be targeted to reverse age-associated IR.